Cannabis Treatment in Dementia Patients A Phase II, Randomized, Double-blind, Placebo-controlled

Study to Investigate the Efficacy and Safety of Avidekel oil

for the Treatment of Subjects with Agitation related to

Dementia

Hermush Vered MD1, Bar Lev Schleider Lihi2 , Stern Noa MD1, Ore Liora MD, MPH3

1 Geriatric wing, Laniado Hospital, Netanya, Israel 2 Research Department, Tikun Olam LTD, Tel Aviv, Israel 3 Yezreel Valley College, Emek Yezreel, Israel

1

Conflict

Lihi Bar-Lev Schleider is an employee of Tikun Olam, medical cannabis supplier in Israel Not involved in data collection or analysis

We have nothing else to disclose

Interest Statement

of

Background

Dementia:

An acquired syndrome of decline in memory and other cognitive functions sufficient to affect daily life in an alert patient

Progressive and disabling

Not an inherent aspect of aging

Different from normal cognitive lapses

3

Background

Over 35 million individuals currently have Alzheimer’s Disease (AD) worldwide

Prevalence : 6%‒8% of people aged 65+ have AD

Nearly 30% of those aged 85+ have AD

4

Background: Dementia and

Neuropsychiatric Symptoms

Neuropsychiatric symptoms, known to be very common among patients with AD

Reported in more than 80 percent of subjects in most studies

Agitation is one of the most common and challenging symptoms to treat

Occurring in 20-50% of patients with moderate to severe Dementia

Associated with:

Caregiver burden

More rapid AD progression

Increased risk of falls

Weight loss

Mortality

5

Background: Management of

Neuropsychiatric Symptoms

Atypical antipsychotic agents are the preferred medications

For the management of psychosis or agitation

Approximately 20% or more patients respond to active therapy

Patients with inadequate responses may benefit from therapy with

mood stabilizers

or antidepressants alone

or in combination with antipsychotic agents

6

Background: Cannabinoids

Cannabinoids have the ability to

Protect neurons from the harmful impact of beta-amyloid

Reduce phosphorylation of tau protein

Enhance the expression of Neurotrophin

Regenerate nerve cells

Inhibit the activity of Acetylcholinesterase, which improves cholinergic transmission and hinders the development of the disease

Stimulate cannabinoid receptors on microglia cells which leads to a reduction in neural

inflammation

7

The Endocannabinoid System Pathway

CB1 receptors are highly abundant in the CNS

Particularly in cerebral cortex and hippocampus

Essential in learning and memory function

Affected by AD pathology

8

The Endocannabinoid System Pathway

CB2 receptors are more abundant in the cells and tissues of the immune system

Associated with decreases in the production of proinflammatory molecules

In vitro

And with the removal amyloid B plaques in the brain

9

The Endocannabinoid System

Animal model studies

deletion of the CB1 gene is associated with cognitive impairment

Several clinical studies

acute and chronic cannabinoids use are associated with cognitive impairment in

Healthy indiv iduals

Patients population: multiple sclerosis and schizophrenia

10

Cannabis and Dementia

Clinical data supports the beneficial of cannabinoids on behavioral symptoms in

Dementia

Volicer et al., demonstrated amelioration of behavioral symptoms in AD with Dronabinol -

THC analogue

Woodwart and co authors – significant reduction in agitation among Dementia patients

with Dronabinol

Broers and co authors- pilot study, reduction in agitation in THC/CBD oral medication

12

Cannabis and Dementia

In Ruthirakuhan meta-analysis on the natural and synthetic cannabinoids for agitation and

aggression in AD:

7 articles and 1 abstract investigated synthetic cannabinoids or THC for the treatment of

agitation and or aggression in patients with AD

There were no clinical trials reporting on the efficacy of cannabidiol for agitation in

patients with AD.

4 studies included patients with moderate AD

2 studies included patients with more severe stages of AD

13

Cannabis and Dementia

In Ruthirakuhan meta-analysis:

There was no significant benefit of cannabinoids over placebo for the treatment of

agitation

There were no significant differences in change in neuropsychiatric symptoms between

treatment groups

Post hoc analysis: patients with greater AD severity demonstrated greater improvement in

agitation when treated with cannabinoids

14

The Clinical Trial

The Efficacy and Safety of Avidekel oil for the Treatment of Subjects

with Agitation related to Dementia 15

The Hypothesis

Cannabis consumption will reduce behavioral disorders and restlessness in elderly patients with dementia

16

The Investigational Product

The cannabis oil was made out of extract from the Avidekel strain and olive oil

Avidekel oil containing Δ9-THC and CBD in a 1:20 ratio at a concentration of 30% CBD and 1.5% Δ9-THC

Each Avidekel contains about 12 mg CBD and 0.6 mg Δ9-THC

The flowers that were used in making the oils were from one batch of the Avidekel strain

17

The Investigational Product

A titration period of 6 weeks

The initial dose was of 1 drop of oil under the tongue three times a day

The maximal dose 21 drops three times a day, 12.6 mg of Δ9-THC and 252 mg of CBD

If an adverse reaction occurred, the patients were tapered down

18

Study Endpoints

Primary Efficacy Endpoint:

The proportion of subjects achieving a CMAI ≥ 4-point decrease at week 16 compared to bassline

Cohen Mansfield Agitation Inventory CMAI- caregiver rated questionnaire

examines 29 agitated behaviors , on a 7 point scale

Cohen-Mansfield, J.. Agitated behavior in persons with dementia: the relationship between type of behavior, it’s frequency, and it’s distruptiveness. J Psychiatr Res. 2008 Nov; 43(1) 64-69. doi:10.1016/j.jpsychires.2008.02.003

19

Study Endpoints

Secondary Efficacy Endpoints:

Assessment of the proportion of subjects achieving a CMAI ≥ 4-point decrease during the treatment period at each time point

Time to 4 point reduction in CMAI in treatment vs. control

Mean change in CMAI score

Mean change in NPI-NH- Neuropsychiatric Inventory- Nursing Home version

Assessment of BPSD response to the treatment- Behavioral and Psychological symptoms of Dementia

20

Safety Endpoints

Incidence and severity of adverse events (AE) and serious adverse events (SAE)

21

The Study Design

Duration of Treatment:

The duration of study participation for each subject was expected to be 4 months:

a) up to 6 weeks (42 days) of dose titration;

b) another 10 weeks of relatively stable dose administration and assessment.

22

Inclusion Criteria

Male or female subjects > 60 years old

Diagnosis of Dementia (NCD) according to the DSM-V Criteria for at least 6 months prior to

screening

MMSE < 23

Clinically relevant BPSD

operationally defined as Neuropsychiatric Inventory (NPI-NH) -agitation/aggression sub score of

≥3 at screening

Documented history of clinically relevant BPSD

Ability to participate in study evaluation and ingest oral medications

23

Exclusion Criteria

The agitation/aggression is attributable to concomitant medications, environmental

conditions or psychiatric condition

Patients with severe heart disease

Subjects suffering from Epilepsy

Subjects suffering from anxiety disorder

Subjects who had psychotic condition in the past OR suffering from psychosis, Schizophrenia OR family history of Schizophrenia OR any other mental disorder

Patients suffering from alcohol and/or substance abuse

24

Enrollment Results

64 pts were eligible for enrollment

42 assigned to the active treatment

22 assigned to placebo

4 pts withdrew before treatment - 2 from the active treatment and 2 from placebo

8 pts withdrew :

3 d/t difficulty in arriv ing

2 died from unrelated causes

1 d/t patient’s family difficulty

2 d/t other medical problems

25

Enrollment Characteristics

Treatment (N=32)

Placebo (N=20)

P

Gender M F

43.8% 56.2%

25.0% 75.0%

.17

Age (range)

77.9 ± 8.8 (61-95)

80.6 ± 9.5 (64-92)

.30

Number of Medications

6.8 ± 2.8 (0-11)

6.6 ± 3.1 (2-12)

.83

26

Primary Outcome

CMAI reduction of ≥ 4 points at week 16:

χ2 =8.75, P<0.003

Treatment Group 71.9% Placebo Group 30%

27

Secondary Outcome

Baseline CMAI score

Mean SD Treatment Group 57.28 17.34

Placebo Group 58.50 22.27

No statistically significant difference in baseline CMAI between the two groups

(t(50)=0.83, p>.83)

28

Secondary Outcome

Mean change in CMAI score

There was a statistically significant difference in the change between the 2 groups (t(50)=-3.20, p<.002).

Mean Median SD Treatment Group -13.3 -8.0 15.63

Placebo Group -2.3 -1.5 9.13

29

Mean Change in Neuropsychiatric Inventory

(NPI-NH) agitation/aggression sub score

There was no statistically significant difference in baseline agitation level (p>.95)

There was a statistically significant difference in mean change in agitation

Neuropsychiatric Inventory (NPI-NH) agitation/aggression sub score (p <.02)

30

Baseline Level Avg. Decrease Treatment Group 6.0 3.3

Placebo Group 6.09 1.1

Reduction in the number of medications

There was no statistically significant difference in the change

(less/same/more) in the number of medicines at week 16 between the 2 treatment groups (p=.71)

#Medications Treatment

Group Placebo Group

Less 56.25% 52.6% Same 31.25% 26.3% More 12.50% 21.1%

31

Adverse Events (AE) , Serious Adverse Events (SAE)

2 pts died in the treatment group, d/t unrelated causes

Other Adverse Events:

Mild Hyponatremia

Increase in appetite

Pruritus

Hypotension

32

Summary

Neuropsychiatric symptoms, known to be very common among patients with Alzheimer's disease

have been reported in more than 80 percent of subjects in most studies

Agitation is one of the most common and challenging symptom to treat

Occurring in 20-50% of patients with moderate to severe Dementia

Our clinical trial shows that CBD rich cannabis oil can reduce agitation and the behavioral symptoms in dementia

The treatment is safe and efficient

33

34